Suicide is a major public health concern. About 30,000 people die each year by suicide in the USA alone, and about one million people die from it worldwide. Depression is a major risk factor for suicide. Several studies indicate that suicide s also associated with abnormal neurobiology, such as altered serotonin function and signaling mechanisms. Some studies also suggest abnormality of the immune function in depression and suicide. This is based on the observation of increased levels of proinflammatory cytokines, which are major mediators of immune function, in the serum and CSF of depressed and suicidal patients and the observation that administration of cytokines, such as TNF-, to cancer patients induces symptoms similar to those of depression. Some recent studies indicate abnormalities of proinflammatory cytokines in the brain of depressed and suicide subjects. Cytokines and chemokine are important biological mediators of immune function. However, it appears that Toll-like receptors (TLR), which may be the first line of defense against pathogens and tissue damage, are also major mediators of innate immunity. Upon activation by specific ligands, TLRs induce downstream signals that lead to cytokine and chemokine production, which can initiate a localized inflammatory response. In order to examine the role of cytokines and TLRs in depression and suicide, we are proposing a comprehensive study of TLRs, cytokines and chemokines in postmortem brain of depressed and suicide subjects. The proposed studies are also based on our preliminary findings from a gene profile study indicating alteration (up- or down-regulation) of 14 genes in depressed suicide victims. These altered genes include certain cytokines, chemokines and TLRs. The main objectives of our proposed studies are to examine in detail the specific TLR and cytokine genes that are altered in suicide and depressed brain, and if these altered genes are specific to suicide (independent of diagnosis) or these alterations are also shared by non-suicide depressed subjects. To achieve this objective we will conduct a gene profile study in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of four groups of subjects which include: 1) normal controls, 2) depressed suicide, 3) non-depressed suicide, 4) non- suicide depressed subjects. We will then validate these findings by determining the mRNA and protein expression of altered genes, which we find to be about 14 in these subjects. These studies may be significant as they may result in identification of important bio- and vulnerability markers for depression and suicide and may provide useful targets, such as TLR-3, for developing newer therapeutic agents. This may be innovative as it may be the first comprehensive study of cytokines, chemokines and TLRs in depression and suicide and is significant for understanding the pathophysiology of depression and suicidal behavior and its treatment.